Human breast cancer is the predominant malignancy and the leading cause of cancer death in women from Western society, as reported by Miller et al., (eds) BIOLOGY OF FEMALE CANCERS, 31–42 (CRC Press, 1997). According to recent estimation by the American Cancer Society, one in every eight U.S. women will have breast cancer and the disease will kill 43,500 women in 1998.
Several lines of evidence have strongly linked prolactin (PRL) to breast cancer development. It has been reported that the expression level of prolactin receptors (PRLR) is higher in human breast cancer cells compared to normal breast epithelial cells (Reynolds et al., 1997), as well as in surgically removed breast cancer tissues (Touraine, Martini P. et al., Increased Expression Of Prolactin Receptor Gene In Human Breast Tumors Versus Continguous Normal Breast Tissues, (Abstract) 79th Annual Meeting of Endocrine Society, p.113, (1997)). The PRLR levels in malignant breast tissue can be five folds higher over its surrounding normal tissue (see Touraine et al. (1997), supra, making these cells highly sensitive to the stimulation of hPRL. Additionally, it has been suggested that one mechanism of the mitogenic action of estrogen in breast may influence the production and secretion of human prolactin (hPRL), since there is a positive correlation between PRLR, estrogen receptors (ER) or progesterone receptor levels (Sirbasku, 1978; Dixon and Lippman 1986; Lippman an Dickson, 1989). Taken together, these findings lead to a hypothesis that hPRL serves as an autocrine/paracrine growth factor that plays an important role in mammary carcinogenesis (Clevenger, et al., Am. J. Pathology, 146:695–705 (1995); Ginsburg, E. et al., Cancer Res., 55:2591–2595 (1995)).
An association between PRL expression and prostate disease has also been proposed in Wennbo et al., Endocrinol 138:4410–4415 (1997). PRL receptors are found in prostate tissue as reported Aragona et al., Endocrinol. 97:677–684 (1975), and Leake et al., J. Endocrinol., 99:321–328 (1983). In addition,PRL levels has observed that can increase with age (Hammond et al., Clin. Endocrinol., 7:129–135 (1977), Vekemans etal., Br. Med. J. 4:738–739 (1975)) coincident with the development of prostate hyperplasia. Transgenic mice overexpressing the PRL gene developed dramatic enlargement of the prostate gland. (see Wennbo et al. (1977), supra).
In view of its link to both breast and prostate cancer, PRL signaling represents an attractive target for therapeutic intervention. Heretofore, however, no suitable medicaments have been available for this purpose.
Immunological approaches hold great promise in treating cancer. There is ample evidence that cancers express tumor-specific antigen and patients have T cells that can respond to these antigens (Boon, Toward T., A Genetic Analysis of Human Tumor Rejection Antigens, Advances in Cancer Research, 58:177–210 (1992); Urban, J L et al., Tumor Antigens, Annu. Rev. Immuno. 10:617–644 (1992)). Yet, these T cells, in many instances, are anergic or otherwise ineffective in combating the cancer. Thus far, the main effort in immunological approaches for tumor therapy is to augment weak host immune responses to tumor antigens such as by exogenously administering cytokines to the patients.
Among many cytokines used, interleukin 2 (IL-2) has been demonstrated to have promising results. IL-2 is the principal cytokine responsible for progression of T lymphocytes from the G1 to S phase of the cell cycle (see Morgan et al., Science 193:1007–1008 (1979). The principal actions of IL-2 on lymphocytes are as follows: (1) IL-2, as the major autocrine growth factor for T lymphocytes, determines the magnitude of T cell-dependent immune response. (2) IL-2 stimulates the growth of natural killer (NK) cells and enhances their cytolytic effect, as reported in Hendrzak et al., EXPERIMENTAL AND CLINICAL AGENTS, 263–282 Humana Press Inc. (1997).
However, it has been reported that cancer patients receiving systemic IL-2 often experience potentially life-threatening side effects that limits the total amount that can be administered which, in turn, directly affects the efficacy of treatment. (see Rosenberg et al., N. Engl. J. Med. 319:1676–1680 (1988); Maas, Immunobiology 188: 281–292 (1993)). The main efforts regarding the use of IL-2 in tumor therapy, therefore, have been concentrated on ways and means to balance the side effect and the effective dose i.e., increase the specificity of administered IL-2 (target the IL-2 precisely at the tumor site), thereby dramatically decreasing the side effects induced by high systemic dosage.
Forni G., et al., J. Immunol. 138:4033–4041 (1987) demonstrated that injection of a physiological dose of IL-2 directly into tumor caused suppression of their growth. The major advantage of this in situ application is that it decreases toxicity associated with the systemic use of cytokines, but it has the disadvantage of needing to know the exact location of all tumors, which is particularly problematic in patients with widespread metastases.
Further efforts to decrease toxicity have shown that the injection of transfected tumor cells which secrete IL-2 can induce specific T cell-dependent immunity on subsequent challenges by unmodified tumor cells, as reported in Gansbacher et al., J. Exp. Med. 172:1217–1224 (1990); Fearon et al., Cell 60:397–403 (1990); and Pardoll, D. M., Immun. Today 14:310–316 (1993). However, Reisfeld et al., Curr. Top. Microbiol. Immunol. 213:27–53 (1996) note that clinical application of such an approach will be both time consuming and costly, since it will involve the isolation, transfection, and re-administration of an individual patient's tumor cells.
Recently, an alternative approach of using the binding specificity of anti-tumor monoclonal antibodies (mAb) to direct cytokines to tumor sites has been introduced. See Reisfeld et al.(1996), supra. This approach combines the unique targeting ability of a mAb with the multifunctional activities of cytokines, therefore, achieving an effective concentration of IL-2 in the tumor microenviroment. Targeted IL-2 therapy can completely eradicate disseminated pulmonary and hepatic murine melanoma metastases in immunocompetent, syngeneic mice, as shown in Gillies et al., Proc. Natl. Acad. Sci. USA 89:1428–1432 (1992); and Sabzevari et al., Proc. Natl. Acad. Sci. USA 91:9626–9630 (1994).
There are advantages of this targeted IL-2 therapy. For instance, this therapy does not require the mAb-IL-2 fusion protein to reach all target cells to achieve the maximum effects as in the case of other mAb targeted therapies since it is not a direct cytotoxic reaction. Reisfeld et al. (1996), supra. Most importantly, the therapeutic effect of targeted IL-2 therapy is associated with the induction of a long-lived and transferable, protective tumor immunity. This mAb targeted IL-2 therapy is also different and advantageous from ex vivo transfer of cytokine genes, since it concentrates IL-2 in the tumor environment in a non-personalized, making this approach more clinically feasible.
Although the targeted immunotherapy approach shows promise in treating cancer, the therapeutic benefits of combining the effects of antagonizing PRL and targeted IL-2 is unknown in treating cancer. There is, therefore, an unmet need to develop agents and therapies for simultaneously antagonizing the role of PRL in cancer maintenance or proliferation and augmenting the patient's immune response to the cancer.